Cholesterol-lowering therapy

ABSTRACT

Methods are described for preventing or reducing the risk of a first occurrence of a cardiovascular event using an HMG-CoA reductase inhibitor alone or in combination with another lipid altering agent. Subjects to be treated are those having an average serum total cholesterol level, an average to mildly elevated serum low-density lipoprotein cholesterol level, and a below average serum high-density lipoprotein cholesterol level, with no history of clinically evident coronary disease.

FIELD OF THE INVENTION

[0001] The instant invention involves a method of using a cholesterolreducing agent such as a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitor (or HMG-CoA RI) alone or in combination with otherlipid altering agents for preventing or reducing the risk of firstoccurrence of a cardiovascular event.

BACKGROUND OF THE INVENTION

[0002] It has been clear for several decades that elevated bloodcholesterol is a major risk factor for coronary heart disease (CHD), andmany studies have shown that the risk of CHD events can be reduced bylipid-lowering therapy. Prior to 1987, the lipid-lowering armamentariumwas limited essentially to a low saturated fat and cholesterol diet, thebile acid sequestrants (cholestyramine and colestipol), nicotinic acid(niacin), the fibrates and probucol. Unfortunately, all of thesetreatments have limited efficacy or tolerability, or both. With theintroduction of lovastatin, the first inhibitor of HMG-CoA reductase tobecome available for prescription in 1987, for the first time physicianswere able to obtain comparatively large reductions in plasma cholesterolwith very few adverse effects.

[0003] Recent studies have unequivocally demonstrated that lovastatin,simvastatin, and pravastatin, which are members of the HMG-CoA reductaseinhibitor class, slow the progression of atherosclerotic lesions in thecoronary and carotid arteries. Simvastatin and pravastatin have alsobeen shown to reduce the risk of coronary heart disease events inpatients with hypercholesterolemia and/or CHD, and in the case ofsimvastatin a highly significant reduction in the risk of coronary deathand total mortality has been shown by the Scandinavian SimvastatinSurvival Study. This study also provided evidence for a reduction incerebrovascular events. Additional studies have shown that HMG CoA RI'smay have an effect on platelet aggregation.

SUMMARY OF THE INVENTION

[0004] One object of the instant invention is to provide a novel methodfor preventing or reducing the risk of a first occurrence of acardiovascular event in a subject having an average to mildly elevatedlevel of LDL cholesterol, and below average high-density lipoprotein(HDL) cholesterol, with no clinical evidence of coronary heart disease,comprising administering a prophylactically effective amount of a lipidaltering agent such as an HMG-CoA reductase inhibitor either alone or incombination with another lipid altering agent such as a fibrate, orniacin to the subject. Additional objects will be evident from thefollowing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0005] Examples of HMG-CoA reductase inhibitors that may be used includebut are not limited to lovastatin (MEVACOR®; see U.S. Pat. No.4,231,938), simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784),pravastatin (PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin(LESCOL®; see U.S. Pat. No. 5,354,772), atorvastatin (LIPITOR®; see U.S.Pat. No. 5,273,995) and cerivastatin (also known as rivastatin; see U.S.Pat. No. 5,177,080), and the pharmaceutically acceptable salt, ester andlactone forms thereof. The structural formulas of these and additionalHMG-CoA reductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (Feb. 5, 1996). The HMG-CoA RI isselected from lovastatin, cerivastatin, atorvastatin, pravastatin andsimvastatin, a sub-class comprises simvastatin and lovastatin. Examplesof fibrates that may be used in combination with the HMG-CoA RI include,but are not limited to benzofibrate, ciprofibrate, fenofibrate,gemfibrazol and clofibrate.

[0006] The term HMG-CoA reductase inhibitor is intended to include allpharmaceutically acceptable salt, ester and lactone forms of compoundswhich have HMG-CoA reductase inhibitory activity, and therefore the useof such salts, esters and lactone forms is included within the scope ofthis invention.

[0007] Compounds which have inhibitory activity for HMG-CoA reductasecan be readily identified by using assays well-known in the art. Forexample, see the assays described or cited in U.S. Pat. 4,231,938 atcol. 6, and WO 84/02131 at pp. 30-33.

[0008] Ester derivatives of the described compounds may act as prodrugswhich, when absorbed into the bloodstream of a warm-blooded animal, maycleave in such a manner as to release the drug form and permit the drugto afford improved therapeutic efficacy.

[0009] Herein, the term “pharmaceutically acceptable salts” shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base. Examples of such salts include, but are not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,oleate, oxalate, pamaote, palmitate, panthothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide, valerate.

[0010] Prophylactically effective amounts of the HMG-CoA reductaseinhibitors are suitable for use in the compositions and methods of thepresent invention. The term “prophylactically effective amount” isintended to mean that amount of a pharmaceutical drug that will preventor reduce the risk of occurrence of the biological or medical event thatis sought to be prevented of a tissue, a system, animal or human that isbeing sought by a researcher, veterinarian, medical doctor or otherclinician. The dosage regimen utilizing an HMG-CoA RI is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the subject; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the subject; and the particular compound or salt orester thereof employed. A consideration of these factors is well withinthe purview of the ordinarily skilled clinician for the purpose ofdetermining the prophylactically effective amounts of the drug needed toprevent or reduce the risk of occurrence of the condition sought to beprevented. In one embodiment, the prophylactically effective amount tobe used in the methods of this invention is that amount of drugsufficient to lower the human subject's LDL cholesterol to a targetlevel of 130 mg/dl or less; in a sub-embodiment to a target level of 115mg/dl or less; and in a further sub-embodiment to a target level of 110mg/dl or less. The ordinarily skilled clinician will be able to titratethe subject to the appropriate amount of lipid altering agent such as anHMG-CoA RI which, when taken on a daily basis, will allow the patient toreach this goal.

[0011] The term “patient” or “subject” includes mammals, especiallyhumans, who take a lipid altering agent for any of the uses describedherein. Administration of the lipid altering agent to the subjectincludes both self-administration and administration to the subject byanother person.

[0012] Dosage information for HMG-CoA RI's is well known in the art,since several are marketed in the U.S. In particular, the daily dosageamounts of the HMG-CoA reductase inhibitor may be the same or similar tothose amounts which are employed for anti-hypercholesterolemic treatmentand which are described in the Physicians' Desk Reference (PDR). Forexample, see the 50^(th) Ed. of the PDR, 1996 (Medical Economics Co); inparticular, see at page 216 the heading “Hypolipidemics,” sub-heading“HMG-CoA Reductase Inhibitors,” and the reference pages cited therein.Preferably, the oral dosage amount of HMG-CoA RI is from about 1 to 200mg/day, and more preferably from about 5 to 160 mg/day. However, dosageamounts will vary depending on the potency of the specific HMG-CoAreductase inhibitor used as well as other factors as noted above. AnHMG-CoA RI which has sufficiently greater potency may be given insub-milligram daily dosages.

[0013] As examples, the daily dosage amount for simvastatin may beselected from 5 mg, 10 mg, 20 mg, 40 mg, and 80 mg; for lovastatin, 10mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The dailydosage amount for cerivastatin may be in the range of from 0.1 mg to 0.8mg, and more particularly from 0.2 mg to 0.8 mg, including dosageamounts of 0.2 mg, 0.3 mg, 0.4 mg and 0.8 mg. Oral administration may bein single or divided doses of two, three, or four times daily, althougha single daily dose of the HMG-CoA RI is preferred.

[0014] Pharmaceutical formulations for HMG-CoA reductase inhibitors arewell-known to those skilled in the art, as evidenced by the informationprovided in the 1996 PDR. While the HMG-CoA reductase inhibitor can beadministered orally or parenterally, oral dosing is preferred.

[0015] For example, the active agents employed in the instant therapycan be administered in such oral forms as tablets, capsules (each ofwhich includes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions, syrups, andemulsions. Oral formulations are preferred. The instant inventionincludes the use of oral rapid-release as well as time-controlledrelease pharmaceutical formulations, particularly as described in U.S.Pat. No. 5,366,738.

[0016] The active drug can be administered in admixture withpharmaceutical diluents, excipients or carriers (collectively referredto herein as “carrier” materials) suitably selected with respect to theintended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices. See, for example, Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa.

[0017] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesium stearate,steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharmaceutically acceptableinert carrier such as ethanol, glycerol, water and the like. Moreover,when desired or necessary, suitable binders, lubricants, disintegratingagents and coloring and flavoring agents can also be incorporated intothe mixture. Stabilizing agents such as antioxidants (BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. Other suitable components include gelatin, sweeteners,natural and synthetic gums such as acacia, tragacanth or alginates,carboxymethylcellulose, polyethylene glycol, waxes and the like.

[0018] The active drug can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

[0019] Active drug may also be delivered by the use of monoclonalantibodies as individual carriers to which the compound molecules arecoupled. Active drug may also be coupled with soluble polymers astargetable drug carriers. Such polymers can includepolyvinyl-pyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

[0020] The methods of the invention may be used to prevent or reduce therisk of a first occurrence of a fatal or non-fatal cardiovascular event.The term “cardiovascular event” includes but is not limited to fatal andnon-fatal acute major coronary events, coronary revascularizationprocedures, peripheral vascular disease, stable angina, andcerebrovascular insufficiency such as stroke.

[0021] The term “acute major coronary event” is intended to includefatal myocardial infarction; witnessed and unwitnessed sudden cardiacdeath and sudden death occurring from 1 hour up to 24 hours aftercollapse; non-fatal myocardial infarction including definite acuteQ-wave myocardial infarction, non-Q-wave myocardial infarction, andsilent subclinical (remote) myocardial infarction; and unstable anginapectoris. As used herein, the term “myocardial infarction” is intendedto include both Q-wave and non-Q-wave myocardial infarction and silentsubclinical (remote) myocardial infarction.

[0022] Subjects to be treated with the instant methods are those havingan average to mildly elevated serum total cholesterol level, which isintended herein to be a level less than or equal to about 260 mg/dl. Inparticular, the patients to be treated may have a serum totalcholesterol level of less than or equal to 240 mg/dl, and moreparticularly under 200 mg/dl. For example, the subjects to be treatedmay have a serum total cholesterol level from 180 mg/dl to 264 mg/dl. Inone embodiment, the subjects to be treated have a below averagehigh-density lipoprotein cholesterol level, i.e., less than or equal to50 mg/dl, and an average to mildly elevated low-density lipoproteincholesterol level, i.e., less than or equal to 190 mg/dl, prior totreatment. In another embodiment the low-density lipoprotein cholesterollevel is 130 mg/dl to 190 mg/dl prior to treatment. In a still furtherembodiment, the LDL-cholesterol is <130 mg/dl if the ratio of totalcholesterol to HDL-cholesterol is >6. The subjects to be treated alsohave no clinically evident coronary heart disease.

[0023] In accordance with this invention, a prophylactically effectiveamount of an HMG-CoA RI or a combination with another lipid alteringagent can be used for the preparation of a medicament useful forpreventing or reducing the risk of a first occurrence of acardiovascular event in a subject having an average to mildly elevatedlevel of serum total cholesterol, an average to mildly elevated level oflow-density lipoprotein cholesterol, and a below average level ofhigh-density lipoprotein cholesterol.

[0024] The following is a description of a clinical trial referred toherein as “AFCAPS/TexCAPS” or “AFCAPS” employing lovastatin to exemplifythe methods of the present invention.

EXAMPLE 1

[0025] AFCAPS/TexCAPS was a primary prevention endpoint event trialwhich: (1) included unstable angina as a primary endpoint, reflectingthe trend to treat coronary heart disease aggressively before amyocardial infarction has occurred; 2) involved aggressive pharmacologicintervention, with titration, to target an LDL-cholesterol goal lowerthan current National Cholesterol Education Panel guidelines for primaryprevention; and 3) included a cohort comprised of men and women with abroad age range encompassing the elderly and included persons with alipid profile consisting of average total and LDL-cholesterol, belowaverage HDL-cholesterol levels; total cholesterol/HDL-cholesterol ratiogreater than or equal to 4.5, with a baseline mean ratio of 6.1 for thecohort; and LDL/HDL-cholesterol ratio greater than or equal to 4.

[0026] Entrance inclusion criteria were LDL-cholesterol 130-190 mg/dl(or <130 if the ratio of total cholesterol/HDL is >6) andHDL-cholesterol ≦45 mg/dl for men and ≦47 mg/dl for women.

[0027] The trial was designed to study the effect of LDL-cholesterolreduction in a cohort with average to mildly elevated LDL-cholesteroland a below average HDL-cholesterol. National Cholesterol EducationPanel guidelines for adults (see National Cholesterol Education ProgramExpert Panel, Summary of the second report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation andTreatment of High Blood Cholesterol in Adults (Adult Treatment PanelII), JAMA, 1993;269:3015-3023) already incorporate HDL-cholesterolconcentration in recommendations for estimating CHD risk and selectinglipid-altering therapy.

[0028] Study Design

[0029] AFCAPS/TexCAPS was a double-blind, randomized, placebo controlledtrial designed and powered to investigate whether chroniclipid-lowering, with lovastatin will decrease the rate of first acutemajor coronary events (e.g. sudden cardiac death, fatal and non-fatalmyocardial infarction and unstable angina) compared to intervention withdiet alone during at least 4.5 years of follow-up in a cohort withoutclinical evidence of atherosclerotic cardiovascular disease and withaverage to mildly elevated total cholesterol, average to midly elevatedLDL-cholesterol, and below average HDL-cholesterol. Secondary objectivesincluded whether chronic treatment with lovastatin, compared to placebo,would decrease cardiovascular morbidity and mortality across thespectrum of clinical events, by measuring the rates of: (1) fatal andnon-fatal coronary revascularization procedures (2) unstable angina, (3)fatal and non-fatal myocardial infarction, (4) fatal and non-fatalcardiovascular events, (5) fatal and non-fatal coronary events.

[0030] All participants underwent dietitian taught group instruction inthe American Heart Association Step 1 diet commencing at least 12 weeksprior to randomization (Week -12) and reinforced at Weeks -4 and -2.Baseline observations included collection of medical history, healthhabit and demographic data, physical exam, eye exam (San Antonio cliniconly), chest X-ray, mammogram (women), electrocardiogram and analysis oflipids/lipoproteins, hematology, blood chemistry and urine. A 2-weekplacebo baseline run-in was followed by randomization of eligiblecompliant participants to treatment with lovastatin or placebo.

[0031] Participants included 6605 men and women with normal to mildlyelevated total and LDL-cholesterol and below average HDL-cholesteroldefined as: total cholesterol 180-264 mg/dl, LDL-cholesterol 130-190mg/dl, HDL-cholesterol ≦45 mg/dl for men and ≦47 mg/dl for women andtriglycerides ≦400 mg/dl. All lipid/lipoprotein entrance criteria had tobe met on average at both four and two weeks prior to randomization(after at least eight weeks of diet therapy). In addition, for bothtotal and LDL-cholesterol, the two eligibility determinations had to bewithin 15% of each other.

[0032] Excluded for clinical evidence of atherosclerotic cardiovasculardisease were men and women who had: prior history of myocardialinfarction; angina; claudication; cerebrovascular accident; or transientischemic attack. Also excluded were those aged >73 years or <45 years(men) or <55 years (women) or those with secondary hyperlipoproteinemia,nephrotic syndrome, uncontrolled or insulin-dependent diabetes mellitusor uncontrolled hypertension. At their discretion, investigators alsocould have excluded those who would have difficulty completing a studyof at least 5 years duration (e.g. due to compliance problems or reducedlife expectancy).

[0033] Baseline risk factors in the tested population were as follows:

[0034] Family history of premature coronary artery disease: 16%;

[0035] Active cigarette smoker: 12%;

[0036] Hypertension: 22%;

[0037] Diabetes: 2%.

[0038] HDL <35 mg/dL: 35%

[0039] Participants were randomized to either placebo or lovastatin 20mg once a day and were stratified by center and gender so that there wasan equal chance of being assigned to lovastatin or placebo. Formalprocedures ensured maintenance of the study blind. Participants,investigators, Steering Committee members and those providingparticipant care, monitoring or managing data, or adjudicating endpointswere blinded. For participant safety, an independent Data and SafetyMonitoring Board was not blinded. In addition, two programmers and thestudy statistician who performed analyses for the safety monitoringboard had access to either the allocation schedule or to the unblindedlipid value.

[0040] Baseline measurements on the day of randomization included lipidanalysis (including Apo A1 and Apo B), hematology, blood chemistry andurinalysis.

[0041] During the first 48 weeks of active treatment, participantsreturned to clinic at 6 week intervals. At each visit, participants wereasked about adverse events and underwent laboratory safety tests forliver enzymes and creatine kinase. Every 12 weeks, participants alsoreceive dietary reinforcement. During the first 6 months, a lipidprofile was performed at every visit. At Week 48, participants receiveddietary advice and underwent an extensive evaluation that included thetests routinely done at each visit, as well as physical exam,electrocardiogram, mammography (women), ophthalmological examination(San Antonio clinic only), complete blood chemistry, hematology andurinalysis.

[0042] After Week 48, the interval between visits was longer (Week 60,Month 18, then every 6 months). At week 60 and at all “mid-year” visits,adverse experience inquiry and laboratory safety tests were performed.The year-end visit included all tests and observations described at theWeek 48 visit. At Week 48 and Year 5, Apo A1 and Apo B were measured. Atall protocol visits, pharmacists assessed compliance by pill counts.

[0043] To attempt to achieve an on-treatment LDL-cholesterol of 110mg/dl or lower, participants in the lovastatin treatment group could betitrated to lovastatin 40 mg once a day based upon LDL-cholesterolvalues at 6 and 12 weeks after randomization. Participants in thelovastatin treatment group with LDL-cholesterol >110 mg/dl at bothvisits were titrated at week 18 to 40 mg once a day of lovastatin bytaking two 20 mg tablets once a day. To maintain the blind, an equalnumber of randomly selected participants in the placebo treatment groupwere also titrated to two tablets per day. To maintain the blind, anequal number from the titrated placebo group also had their dosesreduced. Participants were flagged for withdrawal by the unblindedprogrammer, if LDL-cholesterol values >195 mg/dl on successive visitsfollowing titration. The investigator, the participant and thoseinvolved in the participant's care were not unblinded to treatment groupor during double blind.

[0044] The primary endpoint events included sudden cardiac death, fataland non-fatal myocardial infarction and unstable angina. They aredefined as follows:

[0045] I. Fatal Myocardial Infarction or Sudden Cardiac Death

[0046] The definition requires that there be no non-cardiac cause ofdeath and one of the following:

[0047] Fatal Myocardial Infarction—death within 28 days from the onsetof symptoms of a definite acute myocardial infarction

[0048] Witnessed Unexpected Sudden Cardiac Death—within 1 hour ofsymptoms

[0049] Death occurring >1 hour but <24 hours after collapse

[0050] Unwitnessed Unexpected Death, Presumed Sudden—must haveconfirming autopsy data or, if autopsy not performed, preceding historyof CHD events or symptoms

[0051] II. Non-fatal Myocardial Infarction

[0052] Acute Q-Wave Myocardial Infarction—requires definitive ECG

[0053] Acute Non-Q-Wave Myocardial Infarction—definitive ECG or, ifequivocal, enzymes must be diagnostic. Non-Q-Wave Myocardial Infarctionincludes myocardial infarctions reperfused by either mechanical orpharmacologic means providing there is supporting ECGs and enzyme data

[0054] Silent Subclinical (Remote) Myocardial Infarction—definitive ECG,or, if ECG is equivocal, focal wall motion abnormality consistent withmyocardial infarction on rest echo or stress thallium (fixed defect) andon catheterization, a ≧50% stenosis in a major corresponding epicardialvessel. Participants who have had a cardiac catheterization as the firstdiagnostic test for presumed silent (or remote) myocardial infarctionare considered to have met criteria for an endpoint event if thecatheterization findings indicate focal wall abnormalities consistentwith myocardial infarction and 50% stenosis in a corresponding artery

[0055] III. Unstable Angina

[0056] New onset exertional and/or accelerated or rest angina andrequires at least one of the following:

[0057] Stress perfusion study: 1 mm ST segment changes and reversibledefect

[0058] 90% epicardial vessel stenosis or 50% stenosis in the Left Main

[0059] ≧1 mm ST segment changes with pain on stress testing and/orresting ECG and evidence of 50% stenosis in a major epicardial vessel

[0060] Note that ‘angina’ was adjudicated as a secondary endpoint eventif, prior to the hospitalization, the participant was asymptomaticfor >2 weeks or has been stable for >1 month (defined as 28 days) evenif the criteria for ‘unstable angina’, noted above, were met.

[0061] All subjects were followed until the decision to end the studyafter a median duration of 5.2 years of treatment.

[0062] The trial design for the final analysis provided 90 to 97% power,respectively, to detect the reductions in the number of patientsexperiencing as a first event any of those shown in the following Table1: TABLE 1 EFFICACY ENDPOINTS Risk Relative Risk ENDPOINTS Reduction(C.I.) Primary Endpoint: acute 37% 0.63 (0.50, 0.79), major coronaryevents p = 0.00008 defined as fatal and non- fatal myocardialinfarction, unstable angina or sudden cardiac death Secondary EndpointsRevascularizations 33% 0.67 (0.52, 0.85), p = 0.001 Unstable Angina 32%0.68 (0.48, 0.95), p = 0.023 Fatal and Nonfatal MI 40% 0.60 (0.43,0.83), p = 0.002 Fatal and Nonfatal 25% 0.75 (0.62, 0.91),Cardiovascular Events p = 0.003 Fatal and Nonfatal 25% 0.75 (0.61,0.92), Coronary Events p = 0.006

[0063] Thus, the risk of an acute major coronary event using lovastatinwas reduced by at least about 20% and more particularly about 21% to50%, and illustratively about 30% to 40%. The risk reduction of an acutemajor coronary event with simvastatin, pravastatin, fluvastatin,cerivastatin, or atorvastatin is also expected to be at least about 20%,and more particularly about 21% to 50%, and illustratively about 30% to40%.

[0064] Similarly, the risk of a fatal and non-fatal cardiovascular eventusing lovastatin was reduced by at least about 9% and more particularlyabout 9% to 38%, and illustratively about 20% to 30%. The risk reductionof a fatal or non-fatal cardiovascular event with simvastatin,pravastatin, fluvastatin, cerivastatin or atorvastatin is also expectedto be at least about 9%, and more particularly about 9% to 38%, andillustratively about 20% to 30%.

[0065] Also, the risk of unstable angina using lovastatin was reduced byat least about 5% and more particularly about 5% to 52%, andillustratively about 25% to 40%. The risk reduction of unstable anginawith simvastatin, pravastatin, fluvastatin, cerivastatin, oratorvastatin is also expected to be at least about 5%, and moreparticularly about 5% to 52%, and illustratively about 25% to 40%.

[0066] Also, the risk of revascularization using lovastatin was reducedby at least about 15% and more particularly about 15% to 48%, andillustratively about 30% to 40%. The risk reduction of revascularizationwith simvastatin, pravastatin, fluvastatin, cerivastatin, oratorvastatin is also expected to be at least about 15%, and moreparticularly about 15% to 48%, and illustratively about 30% to 40%.

[0067] Similarly, the risk of a fatal or non-fatal myocardial infarctionusing lovastatin was reduced by at least about 17% and more particularlyabout 17-57%, and illustratively, about 30-50%. The risk reduction of afatal or non-fatal myocardial infarction using simvastatin, pravastatin,fluvastatin, cerivastatin or atorvastatin is also expected to be atleast about 17%, and more particularly about 17-57%, and illustratively,about 30-50%.

[0068] To further evaluate the effect of treatment, risk reduction forfirst acute major coronary events (the primary endpoint) wasinvestigated by LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C)tertiles at the time of randomization. The results are shown in thefollowing Table 2 (with 95% confidence interval, or 95% C.I.), where “%change” indicates the change in LDL-C or HDL-C, as appropriate, frombaseline to the one year point: TABLE 2 % Risk Relative Risk changeReduction (95% C.I.) LDL-C (mg/dl) <142 −20.1 34% 0.66 (0.43, 1.00)  142.0-156.8 −26.0 36% 0.64 (0.42, 0.99) >156.9 −28.9 41% 0.59 (0.41,0.85) HDL-C (mg/dl) <34.0    7.4 45% 0.55 (0.38, 0.82)   34.5-39.5   6.2 43% 0.57 (0.39, 0.84) >39.5    4.3 15% 0.85 (0.54, 1.32)

[0069] The risk reduction achieved with lovastatin was independent ofbaseline LDL-C and HDL-C, thus demonstrating that benefit is conferredeven in those subjects in the lowest LDL-C tertile. Similar results arealso expected to be achieved with simvastatin, pravastatin, fluvastatin,cerivastatin and atorvastatin.

[0070] While the invention has been described and illustrated withreference to certain particular embodiments thereof, those skilled inthe art will appreciate that various changes, modifications andsubstitutions can be made therein without departing from the spirit andscope of the invention. For example, effective dosages other than theparticular dosages as set forth herein above may be applicable as aconsequence of variations in the responsiveness of the mammal beingtreated for any of the indications for the active agents used in theinstant invention as indicated above. Likewise, the specificpharmacological responses observed may vary according to and dependingupon the particular active compound selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

What is claimed is:
 1. A method for preventing or reducing the risk of afirst occurrence of a cardiovascular event comprising administering aprophylactically effective amount of an HMG-CoA reductase inhibitoralone or in combination with another lipid altering agent to a subjecthaving a serum high-density lipoprotein cholesterol level less than orequal to 50 mg/dl prior to treatment.
 2. The method of claim 1 whereinthe subject has an average level of serum low-density lipoproteincholesterol prior to treatment.
 3. The method of claim 2 wherein thesubject has a low-density lipoprotein cholesterol level less than orequal to 190 mg/dl prior to treatment.
 4. The method of claim 1 whereinthe subject has an average level of serum total cholesterol prior totreatment.
 5. The method of claim 1 wherein the subject has a serumtriglycerides level of less than or equal to 400 mg/dl prior totreatment.
 6. The method of claim 1 wherein the subject has a ratio oftotal cholesterol/HDL-cholesterol of greater than or equal to 4.5. 7.The method of claim 1 wherein the subject has no history of clinicallyevident coronary heart disease.
 8. The method of claim 7 wherein thesubject has an average level of serum low-density lipoproteincholesterol and an average level of serum total cholesterol prior totreatment.
 9. The method of claim 8 wherein the subject has a ratio oftotal cholesterol/HDL-cholesterol of greater than or equal to 4.5. 10.The method of claim 9 wherein the subject has a serum triglycerideslevel of less than or equal to 400 mg/dl prior to treatment.
 11. Themethod of claim 1 wherein the prophylactically effective amount of theHMG-CoA reductase inhibitor is an amount sufficient to lower thesubject's low-density lipoprotein cholesterol level to 130 mg/dl orless.
 12. The method of claim 11 wherein the prophylactically effectiveamount of the HMG-CoA reductase inhibitor is an amount sufficient tolower the treated subject's low-density lipoprotein cholesterol level to115 mg/dl or less.
 13. The method of claim 12 wherein theprophylactically effective amount of the HMG-CoA reductase inhibitor isan amount sufficient to lower the treated subjectt's low-densitylipoprotein cholesterol level to 110 mg/dl or less.
 14. The method ofclaim 1 wherein the subject has a serum total cholesterol level lessthan or equal to 260 mg/dl.
 15. The method of claim 1 wherein thesubject is female and at least 55 years old and has a serum high-densitylipoprotein cholesterol level less than or equal to 47 mg/dl prior totreatment.
 16. The method of claim 1 wherein the subject is male and atleast 45 years old and has a serum high-density lipoprotein cholesterollevel less than or equal to 45 mg/dl prior to treatment.
 17. The methodof claim 1 wherein the reduction of risk of a first occurrence of acardiovascular event is at least about 10%.
 18. The method of claim 17wherein the reduction of risk of a first occurrence of a cardiovascularevent is at least about 20-30%
 19. The method of claim 1 wherein thesubject is administered a prophylactically effective amount of anHMG-CoA reductase inhibitor regularly for at least 1 year.
 20. Themethod of claim 19 wherein the subject is administered aprophylactically effective amount of an HMG-CoA reductase inhibitorregularly for at least 2 years.
 21. The method of claim 20 wherein thesubject is administered a prophylactically effective amount of anHMG-CoA reductase inhibitor regularly for at least 4.5 years.
 22. Themethod of claim 1 wherein the cardiovascular event is selected from thegroup consisting of fatal and non-fatal acute major coronary events,coronary revascularization procedures, peripheral vascular disease,stable angina, and cerebrovascular accidents.
 23. The method of claim 22wherein the cardiovascular event is selected from the group consistingof fatal and non-fatal acute major coronary events and coronaryrevascularization procedures.
 24. The method of claim 23 wherein thefatal and non-fatal acute major coronary events are selected from thegroup consisting of fatal myocardial infarction; witnessed andunwitnessed sudden cardiac death and sudden death occurring from 1 hourup to 24 hours after collapse; non-fatal myocardial infarction; definiteacute Q-wave myocardial infarction; non-Q-wave myocardial infarction;silent subclinical (remote) myocardial infarction; and unstable anginapectoris.
 25. The method of claim 1 wherein the HMG-CoA reductaseinhibitor is selected from the group consisting of lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin andthe pharmaceutically acceptable salt, ester and lactone forms thereof.26. The method of claim 25 wherein the HMG-CoA reductase inhibitor isselected from the group consisting of lovastatin and simvastatin.
 27. Amethod for preventing or reducing the risk of a first occurrence of acardiovascular event by at least 20-30% comprising administering aprophylactically effective amount of an HMG-CoA reductase inhibitor to asubject having, prior to treatment, a serum high-density lipoproteincholesterol level less than or equal to 50 mg/dl, a serum low-densitylipoprotein cholesterol level less than or equal to 190 mg/dl, a serumtotal cholesterol level less than or equal to 260 mg/dl, a ratio oftotal cholesterol/HDL-cholesterol of greater than or equal to 4.5, andno history of clinically evident coronary heart disease.
 28. The methodof claim 27 wherein the prophylactically effective amount of the HMG-CoAreductase inhibitor is an amount sufficient to lower the subject'slow-density lipoprotein cholesterol level to 130 mg/dl or less.
 29. Themethod of claim 28 wherein the prophylactically effective amount of theHMG-CoA reductase inhibitor is an amount sufficient to lower thesubject's low-density lipoprotein cholesterol level to 115 mg/dl orless.
 30. The method of claim 29 wherein the prophylactically effectiveamount of the HMG-CoA reductase inhibitor is an amount sufficient tolower the subject's low-density lipoprotein cholesterol level to 110mg/dl or less.
 31. The method of claim 27 wherein the cardiovascularevent is selected from the group consisting of fatal and non-fatal acutemajor coronary events, coronary revascularization procedures, peripheralvascular disease, stable angina, and cerebrovascular accidents.
 32. Themethod of claim 31 wherein the cardiovascular event is selected from thegroup consisting of fatal and non-fatal acute major coronary events andcoronary revascularization procedures.
 33. A method of reducing the riskof an acute major coronary event or a coronary revascularizationprocedure in a human subject with average to mildly elevated LDLcholesterol, below average HDL cholesterol and no symptomaticcardiovascular disease which comprises the administration of aprophylactically effective amount of an HMG-CoA reductase inhibitor. 34.The method of claim 33 wherein the acute coronary event is selected frommyocardial infarction, unstable angina and sudden cardiac death.
 35. Themethod of claim 33 where the acute coronary event is selected frommyocardial infarction and unstable angina.
 36. The method of claim 33wherein the HMG-CoA reductase inhibitor is selected from lovastatin,simvastatin, fluvastatin, cerivastatin and atorvastatin.
 37. The methodof claim 36 wherein the HMG-CoA reductase inhibitor is lovastatin orsimvastatin.
 38. The method of claim 34 wherein the HMG-CoA reductaseinhibitor is selected from lovastatin, simvastatin, fluvastatin,cerivastatin and atorvastatin.
 39. The method of claim 38 wherein theHMG-CoA reductase inhibitor is lovastatin or simvastatin.